Background & Aims Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods We performed a genome-wide association study using 822,927 single-nucleotide polymorphism (SNP) markers from 201 White European and US cases of AC-DILI and 532 population controls, matched for genetic background. Results AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with a human leukocyte antigen (HLA) class II SNP (rs9274407, P=4.8×10−14), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10−4). An independent association was observed in the class I region (rs2523822, P=1.8×10−10), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=0.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10−6) and HLA-DQB1*0602 (P=5×10−10), and their interaction (P=0.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of auto-immunerelated genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10−4). Conclusions Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI, but have limited utility as predictive or diagnostic biomarkers because of the low positive-predictive values.

BACKGROUND & AIMS We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior to May 2009 in Europe (n=137) or the USA (n=274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the USA and South America. For the GWAS, we included only cases of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs). After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% CI, 1.9–3.8; P=2.4×10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6–2.5; P=9.7×10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant, genome wide, for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the LRBA gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6–2.7; P=4.8×10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR=5.4; 95% CI, 3.0–9.5; P=7.1×10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non–drug-specific risk factors.

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Besides antipsychotics, several drugs can induce parkinsonism. We review spontaneous notifications of drug-induced or -worsened parkinsonism to a French regional pharmacovigilance center between 1993 and 2009. During these 17 years, 20,855 adverse drug reactions have been reported, including 155 (0.7%) cases of drug-induced or -worsened parkinsonism. Most of the notifications have involved aged patients (48% between 60 and 79 years) and females (60%). "Seriousness" was found in 43.9% of cases. Worsening of parkinsonism occurred in 28 patients suffering from idiopathic Parkinson's disease. Sixty-nine percent of drug-induced or -worsened parkinsonism cases were observed during the first 3 months after introduction of the "suspect" drug (involving mainly central dopaminergic antagonists). A second peak (20%) was found 12 months after drug introduction (mainly caused by calcium channel blockers). The most frequently reported parkinsonian symptom was rigidity (78.7%). The three cardinal symptoms were found in 37.4% of notifications. Evolution was favorable (after partial or complete withdrawal of suspect drug[s]) in 88.7% of cases. Among the 261 suspect drugs, most involved central dopaminergic antagonists (49%), followed by antidepressants (8%), calcium channel blockers (5%), peripheral dopaminergic antagonists (5%), and H1 antihistamines (5%). Cases with lithium, valproic acid, amiodarone, anticholinesterases, or trimetazidine were also found. Three notifications were the result of pharmacokinetic interactions. We found that drug-induced or -worsened parkinsonism is an often "serious," but reversible, adverse drug reaction. It occurred more frequently between 60 and 79 years. Rigidity was the most frequently reported symptom. Approximately 50% of drug-induced or -worsened parkinsonism cases spontaneously reported were related to drugs other than antipsychotics. Drug-induced or -worsened parkinsonism can also be explained by pharmacokinetic drug interactions.

Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population. Lancet diabetes & endocrinology.